Circuit Diagrams

Project Summary/Abstract Learning how spontaneous neuronal activity shapes embryonic brain development is critical for understanding neurodevelopmental processes, with implications in neurological or neuropsychiatric disorders. Early sporadic activity is essential for the formation of mature correlated neuronal networks. To date, we have had success in identifying the motor circuit as the first circuit to function in a developing zebrafish embryo. In addition, a few neurons, the “leader cells”, are the first neurons to obtain spontaneous neuronal activity.

PROJECT SUMMARY Serotonin has been long been recognized as an important modulator of mood and behavior, yet it projection- specific dynamics are little understood. While serotonin has been well studied in anxiolytic contexts, activity of certain serotonin projections works to increase stress behaviors. In particular, serotonergic projections from dorsal raphe to the anterodorsal bed nucleus of the stria terminalis have been shown to be anxiogenic.

PROJECT SUMMARY A core feature of a number of psychiatric illnesses is the disordered estimation of the predictive relationship between a given cue and an outcome. This failure to appraise and generate appropriate behavioral responses is true for cues that both are rewarding and aversive. For example, in post-traumatic stress disorders innocuous stimuli can elicit intense aversive motivational responses even though these were encountered in a safe and familiar context.

Project Summary/Abstract Electromagnetic brain stimulation is a safe and proven way of controlling neural activity non-invasively with no implanted hardware or injected biochemical agents. Transcranial magnetic stimulation (TMS) is FDA approved for treatment of drug resistant depression and obsessive compulsory disorder with a range of other clinical applications under investigation.

PROJECT SUMMARY Living organisms interact with complex environments that are inherently multisensory. Within these environments, the brain must integrate information from multiple sensory modalities, including the auditory and olfactory systems, for perception and behavior. However, despite the ubiquity and importance of multisensory integration, there is a critical gap in our understanding of how the brain integrates auditory and olfactory stimuli. This proposal will fill this knowledge gap by revealing the mechanisms underlying auditory-olfactory integration in the auditory cortex.

Project Summary / Abstract Astrocytes are pervasive throughout the CNS and are the most abundant non-neuronal cell type. They are an essential component of neural circuits, and increasing evidence demonstrates they are specialized for specific brain regions. For example, proteomic, transcriptomic, and electrophysiology experiments show that hippocampal and striatal astrocytes are distinct. However, it is unknown if astrocytes are heterogeneous within brain regions such as the striatum where neuronal subtypes are largely uniform.

Project Summary We propose to leverage new and existing transcriptomic and epigenetic datasets from mouse, marmoset, macaque and human brain to develop refined approaches for brain cell type enhancer selection for creating cell- type specific enhancer adeno-associated viruses (AAVs), and to make inroads toward prediction of brain-wide expression specificity.

Systematic experimental access to diverse neuronal cell types is a prerequisite to deciphering brain circuit organization, function, and dysfunction. Thus fundamental progress in neuroscience urgently needs cell type access technologies that are specific, comprehensive, easy to use, affordable, scalable, and general across animal species. Most if not all current genetic approaches to cell type targeting are based on genome and DNA engineering, which has inherent limitations in achieving the desired tool features.

PROJECT SUMMARY: This team initiative will provide the broad neuroscience community with a cell type-specific adeno- associated virus (AAV) armamentarium for easy and non-invasive implementation of novel and emerging molecular tools for anatomical and functional analysis of the nervous system in rodents, non-human primates, and human organoids. We will characterize engineered AAV capsids for cell type- and brain region-specific gene delivery (Aim 1).

Project Summary / Abstract A fundamental goal in neuroscience is understanding how neural network function arises from circuit structure. However, the immense complexity of most brain networks has been a significant barrier to progress. We do not have a comprehensive wiring diagram for any mammalian local circuit, much less a whole brain. We do not yet have a comprehensive list of cell types and how they are defined for even the simplest mammalian neuronal circuit.